The invention relates to a combination of dehydroepiandrosterone and aromatase inhibitors as well as the new use of dehydroepiandrosterone (DHEA) in combination with aromatase inhibitors for the production of a pharmaceutical agent for treating a relative and/or absolute androgen deficiency in men.
In men, increasing age leads to a reduction of testicular androgen production and androgen concentration in the organism, as well as, in men-and women equally, to a reduction of adrenal production of dehydroepiandrosterone, a hormonal precursor for androgens and estrogens. In contrast to the situation in women, in whom estrogen production drops to castration values within a comparatively short period, this takes decades in men and involves an only gradual drop. It can nevertheless be clearly demonstrated that the total concentration of testosterone in the serum in the higher age group is significantly reduced compared to the values in young men. Because of the increase in steroid hormone-binding globulin (SHBG) that coincides with the aging process, moreover, the proportion of free, unbound, and thus biologically active testosterone drops. In addition, it is clear that the serum levels of estrogens, although they are produced from androgens by direct conversion, do not drop in the same way as a function of age. As a result, the hormonal environment is significantly altered.
In men, the hormonal environment of the sexual steroids is characterized by a significant preponderance of androgens over estrogens. While the circulating main component of androgens, testosterone, is detected in the serum in units in the range of nmol/l the estrogen antagonist, estradiol, can be measured only in the range of pmol/l. This considerable preponderance of androgen can be detected basically in the entire late puberty period of life, but there is a clearly different intensity of this androgen dominance as a function of age. With increasing age and particularly so in those over the age of 60, there is a less pronounced emphasis of the androgen preponderance. Table 1 shows published test series in which the ratio of testosterone serum to estradiol serum was determined in a comparison of young to old men (xe2x89xa760 years).
Although in the above-mentioned works, the ratio of testosterone to estradiol is indicated to some extent in considerably different orders of magnitudesxe2x80x94which can be attributed to the different measuring methods that are usedxe2x80x94in older men there is clear agreement between the relative decreases in the preponderance of testosterone by 30-50% and the previous values found in young men.
The relative testosterone deficiency that occurs can have a disadvantageous effect in many respects. It is assumed that, e.g., an imbalance between androgens and estrogens that accompanies the drop in testosterone, generally at, for example, constant estrogen concentrations, is of decisive importance for the occurrence of benign prostatic hyperplasia (BPH). Regardless of the effects of estrogens, however, the relative testosterone deficiency per se can also be regarded as responsible for a number of age-related disorders. Reduction of muscle mass, accompanied by limitation of physical capacity, reduction of bone density and in individual cases even osteoporosis, reduction of libido and potency, and psycho-vegetative disorders can be mentioned here. All above-mentioned disorders are often generically referred to as xe2x80x9cKilmakterium virile. [Male Menopause].xe2x80x9d
The standard treatment for this syndrome, which is presumably caused by androgen deficiency, has been to supply androgens exogenically. Orally active androgens and long-chain testosterone esters with a depot effect that are to be administered intramuscularly are used. These forms of therapy are suitable for improving the symptoms caused by androgen deficiency, but produce an only inadequate approximation of the physiological state.
As a substance to be administered orally, either a testosterone derivative, i.e., not a natural testosterone, is given (e.g., Proviron(R), or the administration is accompanied by a disproportionately large increase in dihydrotestosterone (DHT) that deviates from the physiological situation (e.g., Andriol(R)). Unlike testosterone, DHT seems to be the androgen component that is of great importance for the development of BPH and also of androgenetic alopecia.
In the case of depot formulations, the uneven release from the depot represents a problem that has not yet been satisfactorily resolved; it initially results in an increase in testosterone that extends significantly beyond the normal range, but toward the end of the dosage interval it leads to significantly reduced testosterone values.
It has long been known that, in addition to androgens, estrogens are also involved in the endocrine control circuit that keeps the androgen level in men constant. By administering pharmacological doses of estrogen-active substances, such as, e.g., diethylstilbestrol, it is possible in patients with prostate cancer to largely suppress the hypophyseal LH release and to reduce the testosterone level in the serum to the castration level.
From experience with use of pure antiandrogens in prostate-cancer patients who belong to the same age group as patients with male menopause, the extent of the counterregulatory potential can be assessed. If the central inhibiting action of androgens is suppressed by pure antiandrogens such as flutamide or casodex, in this age group this results in a counterregulatory increase in the serum testosterone concentration by about 50-60% compared to the starting value. In the case of treatment that lasts for months, however, there were indications of a lessening of the activity of counterregulation in the case of the prostate-cancer patients who were treated with pure antiandrogens, i.e., the initially significantly increased androgen levels drop again (Lund and Rasmussen, 1988; Mahler and Denis, 1990: Delaere and Van Thillo, 1991).
It is noteworthy that the reduction in androgens with age is not prevented by activation of the counterregulation mechanism. The reason for this is considered to be that, on the one hand, the testicular function generally diminishes with age, but, on the other hand, the feedback mechanism is also more sensitive to sexual steroids (Deslypere, J. P. et al., Journal of Clinical Endocrinology and Metabolism, 64, No. 1, 1987). Consequently, it has to be assumed that a less pronounced counterregulation is present in older men compared to younger men (see below), and thus for long-term use a serum androgen concentration that is higher than the starting value can be expected.
In contrast, it is known that in younger men, in long-term treatment testosterone values are also effectively increased by daily treatment with antiestrogens (with considerable partial estrogenic action in each case) (Treatment of Male Infertility, Springer-Verlag Berlin, Heidelberg, N.Y. 1982; Fuse, H. et al., Archives of Andrology 31 (1993) 139-145).
Based on theoretical considerations, antiestrogens do not seem well suited for treatment of a relative androgen deficiency in men. Thus, treatment with antiestrogens has no effect on the estrogen level since the antiestrogens block the action of estrogens on their receptor. When antiestrogens are used as receptor blockers, inadequate compliance immediately led to an adverse effect since the higher estrogen concentration can act directly on the now free receptors because of the counterregulation that takes hold.
Another drawback of antiestrogen treatment is the uncertainty as to whether the blocking of estrogen receptors in all estrogen-dependent tissues and organs is equally intense and what significance inherent estrogeneity, such as that of, e.g., the best known antiestrogen tamoxifen, has for use in men.
This invention has the object of providing suitable substances which remedy a relative androgen deficiency (hypoandrogenism) in men while at the same time approximating the physiological hormonal ratio of androgens to estrogens and which avoid the above-mentioned drawbacks.
This object is achieved according to this invention by a combination of dehydroepiandrosterone (DHEA) and aromatase inhibitors as well as by the use of at least one aromatase inhibitor with DHEA for the production of a pharmaceutical agent for treating a relative androgen deficiency in men.
It has been noted that the use of a combination of DHEA and at least one aromatase inhibitor in treating a relative androgen deficiency in older men results in a long-term increase in androgen level.
By gradually lowering the estrogen concentration, a counterregulatory stimulation of androgen synthesis is induced. The extent of the increase in the androgen level by administration of an aromatase inhibitor alone is limited, however, by the DHEA deficiency that is present simultaneously. If the aromatase inhibitor is combined with DHEA substitution, the steroid biosynthesis of the androgens can be more reliably and effectively corrected to normal values. An absolute androgen deficiency can also be eliminated without androgens having to be supplied exogenically. The combination of an aromatase inhibitor with DHEA substitution leads to a synergyxe2x80x94each active ingredient by itself cannot achieve the desired goal as well as the combination does. The difference between the limiting of the aromatase principle of action by the DHEA deficiency and the limiting of DHEA substitution alone is the undesirable increase in the estrogen-biosynthesis rate in men that results in the latter case.
In addition to treating hypoandrogenism in older men, the pharmaceutical combination preparation according to the invention can be used in other indications that result from the deficiency in DHEA and the androgens that follow steroid biosynthesis.
The frequency of cardiovascular diseases, carcinoses, metabolic diseases, as well as susceptibility to infection and the reduction of physical and mental capacity, which become more common with age, can be attributed directly or indirectly to decreasing hormone production. The elimination of the prevailing hormone deficiency by the aromatase +DHEA treatment principle represents an active therapeutic intervention for preventing and treating these typical symptoms of age.
(In this connection, many effects in the animal model and in humans are described solely for DHEA. They include antiproliferative effects, immunomodulatory effects; effects on carbohydrate and lipid metabolism, on body weight, fatty mass and muscle mass, on clotting; effects as regards cardioprotection; effects on the central nervous system, on mitochondrial vesicular breathing, as well as an effect of protecting the cell against the formation of oxygen radicals).
For the purposes of this invention, aromatase inhibitors are all those compounds that prevent estrogens from being formed from their metabolic precursors by inhibiting the enzyme aromatase (inhibition of biosynthesis). As aromatase inhibitors, therefore, all compounds are suitable that are suitable as substrates for aromatase, such as, for example,
the testolactone (17a-oxa-D-homoandrost-1,4-diene-3,17-dione) that is described in the xe2x80x9cJournal of Clinical Endocrinology and Metabolism,xe2x80x9d 49, 672 (1979);
the compounds that are described in xe2x80x9cEndocrinology xe2x80x9d 1973, Vol. 92, No. 3, page 874:
androsta-4,6-diene-3,17-dione,
androsta-4,6-dien-17xcex2-ol-3-one acetate,
androsta-1,4,6-triene-3,17-dione,
4-androstene-19-chloro-3,17-dione,
4-androstene-3,6,17-trione;
the 19-alkynylated steroids that are described in German Laid-Open Specification 31 24 780;
the 10-(1,2,-propadienyl)-steroids that are described in German Laid-Open Specification 31 24 719;
the 19-thio-androstane derivatives that are described in European patent application, publication No. 100 566;
the 4-androsten-4-ol-3,17-dione and its esters that are described in xe2x80x9cEndocrinologyxe2x80x9d 1977, Vol. 100, No. 6, page 1684 and U.S. Pat. No. 4,235,893;
the 1-methyl-15xcex1-alkyl-androsta-1,4-diene-3,17-dione that is described in German Laid-Open Specification 35 39 244;
the 10xcex2-alkinyl-4,9(11)-estradiene derivatives that are described in German Laid-Open Specification 36 44 358 and
the 1,2xcex2-methylene-6-methylene-4-androstene-3,17-dione that is described in European Patent Application 0 250 262.
According to this invention, selective aromatase inhibitors are preferably used in the DHEA/aromatase inhibitor combination and for the production of a pharmaceutical agent for treating a relative androgen deficiency (hypoandrogenism) in men. Selective aromatase inhibitors are defined as those compounds that act as substrates for the aromatase and at the dosage used affect no enzyme other than aromatase in a clinically relevant way.
Regarded as typical selective aromatase inhibitors according to this invention are, for example, the steroidal compounds
1-Methyl-androsta-1,4-diene-3,17-dione (DE-A 33 22 285; atamestane),
4-hydroxy-4-androstene-3,17-dione (formestane) as well as the non-steroidal aromatase inhibitors
(RS)-5-(4-cyanophenyl)-5,6,7,8-tetrahydro-imidazo-(1,5xcex1)-pyridine, hydrochloride (Cancer Res., 48, pp. 834-838, 1988; fadrozole),
4-[cyano-xcex1-(1,2,4-triazol-1-yl)-benzyl]-benzonitrile (CGS 20267),
5-[cyclopentylidene-(1-imidazolyl)-methyl]-thiophene-2-carbonitrile (EP-A 0 411 735; pentrozole),
2,2xe2x80x2-[5-(1Hxe2x80x2,2xe2x80x2,4-triazol-1-yl-methyl)-1,3-phenylene]-bis(2xe2x80x2-methylpropionitrile) (arimidex) and
(6-[1-(4-chlorophenyl)-1,2,4-triazol-1-yl)-methyl]-1-methyl-1H-benzotriazole, dihydrochloride (vorozole).
The list of selective aromatase inhibitors above is not exhaustive; other compounds that are described in the above-mentioned materials and publications, as well as all other compounds that meet the set requirements, are also considered.
Contrary to the assumption that the counterregulatory action could diminish in cases where older men are treated with an aromatase inhibitor over several months, data from longer-term studies, e.g., with atamestane on patients with BPH, show that even after treatment lasting 24 to 48 weeks, there is still a significant increase in testosterone concentration.
Table 2 shows the corresponding results of a 24-week, four-way study in comparison to placebos (100 mg/d, 300 mg/d and 600 mg/d).
Tables 3 and 4 show the results after a 48-week treatment.
Gradual lowering of the estrogen concentration induces a counterregulatory stimulation of androgen synthesis. To a certain extent, there is an endogenic testosterone substitution, by which the androgen/estrogen balance is again brought back to the xe2x80x9cyouthfulxe2x80x9d range. This substantiates the results of the longer-term treatment of older men (average age above 60 years) with the selective aromatase inhibitor atamestane.
In several clinical studies, atamestane was administered at varying dosages and over periods of up to 48 weeks to men in this age group to treat an existing BPH. The results show that with atamestane treatment for patient populations, there was a significant alteration of the testosterone/estradiol ratio in favor of testosterone. Table 5 provides the testosterone/estrogen ratio before and after the administration of atamestane for patient populations from 4 studies and 7 treatment groups.
The administration of atamestane consistently results in a resetting of the testosterone/estradiol balance in favor of the androgenic component. This action was detectable over the entire observation period up to a maximum of 48 weeks of treatment. Although the peripheral estrogen reduction at daily doses of 100 mg-600 mg was equally intense, there was a trend toward greater emphasis of the androgenic proportion at high dosages.
Assuming that the testosterone dominance that was reduced by 30-50% in the age group of patients over 60 years compared to the younger years (relative androgen deficiency) caused the symptoms of xe2x80x9cmale menopause,xe2x80x9d the goal is thus to restore the original xe2x80x9cbalance of powerxe2x80x9d between androgens and estrogens by administering a preferably selective aromatase inhibitor by stimulating endogenic testosterone substitution without the necessity of supplying androgens exogenically. Based on the understanding that the ratio prevailing in age is the result of a 30-50% reduction compared to the youthful values, i.e., is always 50-70% of the previous value, the corresponding xe2x80x9cyouthfulxe2x80x9d previous value can be calculated for each individual patient. A 70-year-old patient with a testosterone/estradiol ratio of 230:1 must accordingly be adjusted to a new balance in the range between 229:1 to 460:1, so that a preceding 30 or 50% reduction is compensated for. Table 6 shows the result of such a calculation for the patient populations of the atamestane studies that are cited in Table 4.
At a daily dose of 100 mg, the target range is generally readily met. At higher dosages, however, the result is somewhat above the target range.
Measuring the serum concentration of testosterone and estradiol can thus give early indication of whether the desired hormone balance was achieved and optionally whether dose adjustment can be undertaken.
Compared to this above-described treatment of hypoadrogenism with at least one aromatase inhibitor by itself (unpublished DE P 44 35 368.5), treatment with DHEA and at least one aromatase inhibitor results in a synergistic effect.
The most important precursor of the androgens testosterone and dihydrotestosterone (DHT) is dehydroepiandrosterone (DHEA), which represents the human sexual steroid with the highest daily rate of synthesis. It is known that with age, the DHEA-plasma level drops to 20% of the maximum values in adolescence.
The combination of DHEA with at least one aromatase inhibitor has, for example, the following advantages:
Because of the synergistic effect, it is possible to reduce the dose of the aromatase inhibitor while maintaining the moderate increase in testosterone and DHT. This avoids side-effects, which can be caused by both active substances.
Because of the synergistic effect, a uniform dose of the aromatase inhibitor results in a more pronounced and reliable increase in testosterone and DHT.
In the case of an absolute androgen deficiency, the latter is actively treated by combining the aromatase inhibitor with DHEA to achieve a synergy. This obviates the need to supply exogenic androgens, with the attendant drawbacks.
Since DHEA and the steroid hormones subsequent to androgen biosynthesis have a specific pharmacological action, the latter can be used when simultaneously combined with an aromatase inhibitor without a simultaneous increase in estrogen biosynthesis occurring, which is undesirable in men.
In addition to the classical physiological role as a hormonal precursor in sexual steroid biosynthesis, numerous effects of DHEA in the animal model and in humans are described. They include antiproliferative effects, immunomodulatory effects, a weight-reducing effect with reduction of fatty mass in favor of muscle mass, an effect on carbohydrate and lipid metabolism, effects on clotting, a cardioprotective action; effects on the central nervous system, on mitochondrial vesicular breathing, as well as an effect of protecting the cell against the formation of oxygen radicals. In a publication by Yen et al. (Effects of Replacement Dose of Dehydroepiandrosterone in Men and Women of Advancing Age. J. Clin. Endocrinol. Metab. 78: 1360-1367, 1994), effects on growth factors are described that can be attributed to the physiological aging of cells. In addition, a more positive effect of DHEA on physical and mental well-being is described there.
DHEA is used in the combination in a daily amount of 10 mg to 100 mg, preferably 20 mg to 60 mg, if the focus is placed on the idea of substitution. In the case of therapeutic use of DHEA with simultaneous administration of an aromatase inhibitor to prevent an increase in the estrogen level, DHEA dosages are on the order of up to 1000 mg within the framework of this invention.
In general, 25 to 500 mg, preferably 50 to 250 mg, of atamestane or a biologically equieffective amount of another aromatase inhibitor is used daily in the combination according to the invention to treat a relative or absolute androgen deficiency in men.
DHEA and the aromatase inhibitors can be administered, e.g., orally or parenterally. For the preferred oral administration, suitable forms are especially tablets, coated tablets, capsules, pills, suspensions, or solutions that can be produced in a way that is commonly used and familiar to one skilled in the art, with the additives and vehicles that are commonly used in galenicals for the formulation of aromatase inhibitors that are to be administered orally.
DHEA and the aromatase inhibitors can be formulated together or separately. When formulated separately, sequential administration is also conceivable.
The pharmaceutical agent that is produced according to the invention contains as an active ingredient per dosage unit the aromatase inhibitor atamestane at a dosage of 25 to 250 mg in addition to the commonly used additives, vehicles and/or diluents or other aromatase inhibitors at biologically equieffective dosages.
In the common dosage unit or in a separate dosage unit, DHEA is contained in an amount of 5 to 200 mg in addition to commonly used adjuvants.
A composition that is typical of a formulation of the aromatase inhibitor atamestane with DHEA as a tablet is presented in Example 2 below.